SOD3 Reduces Inflammatory Cell Migration by Regulating Adhesion Molecule and Cytokine Expression

Juha P Laurila,Lilja E Laatikainen,Maria D Castellone,Mikko O Laukkanen,Eshel Ben-Jacob

doi:10.1371/journal.pone.0005786

Abstract

Inflammatory cell migration characteristic of ischemic damages has a dual role providing the tissue with factors needed for tissue injury recovery simultaneously causing deleterious development depending on the quality and the quantity of infiltrated cells. Extracellular superoxide dismutase (SOD3) has been shown to have an anti-inflammatory role in ischemic injuries where it increases the recovery process by activating mitogen signal transduction and increasing cell proliferation. However, SOD3 derived effects on inflammatory cytokine and adhesion molecule expression, which would explain reduced inflammation in vascular lesions, has not been properly characterized. In the present work the effect of SOD3 on the inflammatory cell extravasation was studied in vivo in rat hind limb ischemia and mouse peritonitis models by identifying the migrated cells and analyzing SOD3-derived response on inflammatory cytokine and adhesion molecule expression. SOD3 overexpression significantly reduced TNFα, IL1α, IL6, MIP2, and MCP-1 cytokine and VCAM, ICAM, P-selectin, and E-selectin adhesion molecule expressions in injured tissues. Consequently the mononuclear cell, especially CD68+ monocyte and CD3+ T cell infiltration were significantly decreased whereas granulocyte migration was less affected. According to our data SOD3 has a selective anti-inflammatory role in ischemic damages preventing the migration of reactive oxygen producing monocyte/macrophages, which in excessive amounts could potentially further intensify the tissue injuries therefore suggesting potential for SOD3 in treatment of inflammatory disorders.

Highlights

The inflammatory process is initiated by endothelial cell (EC) activation comprising upregulation of chemokines and cell adhesion molecules, leukocyte activation and transmigration, and secretion of proinflammatory factors by leukocytes [1]
SOD3 inhibits leukocyte migration in acute ischemia Neutrophils, macrophages, and other inflammatory cells mediate a number of important cellular functions in injured tissue [33,34]
Phagocytotic macrophages clear cellular debris and secrete inflammatory cytokines such as MIP-2, a strong neutrophil attracting agent leading to further increase in inflammatory signaling [35]

Summary

Introduction

The inflammatory process is initiated by endothelial cell (EC) activation comprising upregulation of chemokines and cell adhesion molecules, leukocyte activation and transmigration, and secretion of proinflammatory factors by leukocytes [1]. Among the most potent drugs are glucocorticoids that downregulate the expression of numerous inflammatory chemokines, cytokines and adhesion molecules [3,4,5], which, are not entirely without adverse effects such as delayed myocardial tissue healing, osteoporosis, and blood vessel calcification [6,7,8,9]. Leukocytes are recruited by expression of various cell adhesion molecules, e.g. selectins, and intercellular and vascular cell adhesion molecules (ICAM-1 and VCAM-1, respectively) [15,16]. They promote rolling and firm adhesion of leukocytes to endothelial wall, the necessary interactions preceding transmigration [17]. To aid leukocyte migration the vessel wall cells change their morphology by assuming cytoskeletal and cell-cell junction modifications in response to e.g. ligand binding to ICAM-1 and VCAM-1 [18,19,20], and when stimulated by O22 or TNF-a [21,22]

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Results

Conclusion